Hematological malignancies may derive from either of the two major blood cell lineages: myeloid and lymphoid cell lines. The myeloid cell line normally produces granulocytes, erythrocytes, thrombocytes, macrophages and mast cells; the lymphoid cell line produces B, T, NK and plasma cells. Lymphomas, lymphocytic leukemias, and myeloma are from the lymphoid line, while acute and chronic myelogenous leukemia, myelodysplastic syndromes and myeloproliferative diseases are myeloid in origin.
Examples of malignancies derived from myeloid cells include acute myeloid leukemia, including acute promyelocytic leukemia, and chronic myeloproliferative diseases, including chronic myeloid leukemia.
Malignancies derived from T and NK cells including mature T cell and NK cell neoplasms include T-cell prolymphocytic leukemia, T-cell large granular lymphocytic leukemia, aggressive NK cell leukemia, adult T-cell leukemia/lymphoma, extranodal NK/T cell lymphoma, nasal type, enteropathy-type T-cell lymphoma, hepatosplenic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, blastic NK cell lymphoma, Mycosis Fungoides/Sezary Syndrome, primary cutaneous CD30 positive T-cell lymphoproliferative disorders (primary cutaneous anaplastic large cell lymphoma C-ALCL, lymphomatoid papulosis, borderline lesions), angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma unspecified, and anaplastic large cell lymphoma. B-cell malignancies include B-cell chronic lymphocytic leukemia, mantle cell lymphoma, Burkitt lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, multiple myeloma, Hodgkin's lymphoma, hairy cell leukemia, primary effusion lymphoma and AIDS-related Non-Hodgkin's Lymphoma. Examples of B-cell non-Hodgkin's lymphomas are lymphomatoid granulomatosis, primary effusion lymphoma, intravascular large B-cell lymphoma, mediastinal large B-cell lymphoma, heavy chain diseases (including γ, μ, and a disease), lymphomas induced by therapy with immunosuppressive agents, such as cyclosporine-induced lymphoma, and methotrexate-induced lymphoma. B-cell malignancies comprise more than 85% of diagnosed lymphomas.
Multiple myeloma (MM) is a B-cell malignancy characterized by the latent accumulation of secretory plasma cells in bone marrow with a low proliferative index and an extended life span. The disease ultimately attacks bones and bone marrow, resulting in multiple tumors and lesions throughout the skeletal system. Approximately 1% of all cancers, and slightly more than 10% of all hematologic malignancies, can be attributed to MM. Incidence of MM increases in the aging population, with the median age at time of diagnosis being about 61 years.
Currently available therapies for MM include chemotherapy, stem cell transplantation, Thalomid® (thalidomide), Revlimid® (lenalidomide), Velcade® (bortezomib), Aredia® (pamidronate), and Zometa® (zoledronic acid). Current treatment protocols, which include a combination of chemotherapeutic agents such as vincristine, BCNU, melphalan, cyclophosphamide, adriamycin, and prednisone or dexamethasone, yield a complete remission rate of only about 5%. Median survival is approximately 36-48 months from the time of diagnosis. Recent advances using high dose chemotherapy followed by autologous bone marrow or peripheral blood mononuclear cell transplantation have increased the complete remission rate and remission duration, yet overall survival has only been slightly prolonged, and no evidence for a cure has been obtained. Ultimately, all MM patients relapse, even under maintenance therapy with interferon-alpha (IFN-α) alone or in combination with steroids.
One of the most promising novel agents is the human IgG1 anti-CD 38 monoclonal antibody daratumumab. Daratumumab induces killing of MM cells mainly via the activation of potent cytotoxic immune effector functions, including antibody-dependent cellular cytotoxicity (ADCC), antibody dependent cellular phagocytosis and complement-dependent cytotoxicity (CDC). Another mechanism of action is induction of apoptosis upon secondary cross-linking. Anti-myeloma activity has also been demonstrated in mouse xenograph models and more importantly in a humanized mouse model. Daratumumab has been recently authorized in the US and worldwide under the trade name Darzalex®, as a single agent for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and a immuno modulatory agent or who are double refractory to PI and an immune modulatory agent. Treatment with daratumumab is clinically effective, but there is a marked heterogeneity of response with a fraction of MM patients that does not respond to daratumumab as a single agent. It is currently unknown which mechanisms underlie the differential therapeutic efficacy of daratumumab but the levels of expression of CD38 on the surface of MM cells are positively correlated with the rate of partial clinical response to daratumumab (Nijhof et al., Blood, 15 Jun. 2016; doi:10.1182/blood-2016-03-703439 and Nijhof et al Leukemia, 2039-2049, 2015).
CD38 is a type II membrane protein. It is expressed on most naturally occuring MM malignant plasma cells, and is implicated in various hematological malignancies. CD38 can also be expressed in a variety of malignant hematological diseases of lymphoid lineage, including multiple myeloma, leukemias and lymphomas, such as B-cell chronic lymphocytic leukemia, T- and B-cell acute lymphocytic leukemia, Waldenstrom macroglobulinemia, primary systemic amyloidosis, mantle-cell lymphoma, pro-lymphocytic/myelocytic leukemia, follicular lymphoma, Burkitt's lymphoma, large granular lymphocytic (LGL) leukemia, NK-cell leukemia and plasma-cell leukemia. By contrast, CD38 has been less often reported as implicated in hematological malignancies of myeloid lineage, such as acute or chronic myeloid leukemias. Expression of CD38 has been described on epithelial/endothelial cells of different origin, including glandular epithelium in prostate, islet cells in pancreas, ductal epithelium in glands, including parotid gland, bronchial epithelial cells, cells in testis and ovary and tumor epithelium in colorectal adenocarcinoma. Other diseases, where CD38 expression could be involved, include, e.g., broncho-epithelial carcinomas of the lung, breast cancer (evolving from malignant proliferation of epithelial lining in ducts and lobules of the breast), pancreatic tumors, evolving from the β-cells (insulinomas), tumors evolving from epithelium in the gut (e.g. adenocarcinoma and squamous cell carcinoma), carcinoma in the prostate gland, and seminomas in testis and ovarian cancers. In the central nervous system, neuroblastomas express CD38.
Nevertheless, CD38 is generally not expressed in all patients suffering from some myeloid hematological diseases. It is expected that such CD38-negative cases would a priori not be responsive to anti-CD38 agents.
Thus, there is a need for additional therapies for the treatment of hematological diseases, including those expressing CD38 and those that do not express CD38.